Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia

Abstract

Friedreich ataxia (FRDA), the most common of the inherited ataxias, is an autosomal recessive degenerative disorder, characterized clinically by onset before the age of 25 of progressive gait and limb ataxia, absence of deep tendon reflexes, extensor plantar responses, and loss of position and vibration sense in the lower limbs. FRDA is caused by a GAA triplet expansion in the first intron of the FRDA gene on chromosome 9q13 in 97% of patients. The FRDA gene encodes a widely expressed 210-aa protein, frataxin, which is located in mitochondria and is severely reduced in FRDA patients. Frataxin function is still unknown but the knockout of the yeast frataxin homologue gene (YFH1) showed a severe defect of mitochondrial respiration and loss of mtDNA associated with elevated intramitochondrial iron. Here we report in vivo evidence of impaired mitochondrial respiration in skeletal muscle of FRDA patients. Using phosphorus magnetic resonance spectroscopy we demonstrated a maximum rate of muscle mitochondrial ATP production (V(max)) below the normal range in all 12 FRDA patients and a strong negative correlation between mitochondrial V(max) and the number of GAA repeats in the smaller allele. Our results show that FRDA is a nuclear-encoded mitochondrial disorder affecting oxidative phosphorylation and give a rationale for treatments aimed to improve mitochondrial function in this condition.

Figure 1

Calf muscle ³¹P-MRS spectra. (Upper) Spectra (eight free induction decays) from a normal subject (A) and patient 2 (B) at the end of in-magnet work. (Lower) Spectra (eight free induction decays) collected between 16 and 32 sec of recovery from the same subjects (C, normal subject; D, patient 2). During incremental exercise there is a progressive reduction of the PCr peak, hydrolyzed via the creatine kinase reaction to buffer ATP concentration, and an increase in the P_i peak produced by the ATP hydrolysis during muscle contraction (A and B). As soon the exercise is stopped PCr and P_i concentrations begin to return to their pre-exercise values: PCr is resynthesized from ATP, via the creatine-kinase reaction, and P_i is used for ATP synthesis (C and D). The ATP production during recovery from exercise is entirely caused by oxidative phosphorylation (10), thus the PCr resynthesis rate reflects precisely the mitochondrial rate of ATP production. At the same recovery time point, the PCr peak is smaller in patient 2 (D) than in the control subject (C), indicating a reduced rate of muscle mitochondrial ATP production in the FRDA patient. The abscissa reports the chemical shift in ppm and ordinate the relative signal intensity in arbitrary units.

Figure 2

Deficit of mitochondrial ATP production in skeletal muscle of patients with FRDA. Maximum rate of mitochondrial ATP production (V_max) in 12 FRDA patients compared with 18 controls and 12 diseased controls (DC).

Figure 3

Correlation between skeletal muscle maximum rate of mitochondrial ATP production (V_max) and the number of GAA repeats in the smaller allele in the 12 FRDA patients.